Arylethene-sulfonamides

ABSTRACT

The invention relates to novel aryl-ethene-sulfonamides and their use as active ingredients in the preparation of pharmaceutical compositions. The invention also concerns related aspects including processes for the preparation of the compounds, pharmaceutical compositions containing one or more of those compounds and especially their use as endothelin receptor antagonists.

The present invention relates to novel arylethene-sulfonamides of thegeneral formula I and their use as active ingredients in the preparationof pharmaceutical compositions. The invention also concerns relatedaspects including processes for the preparation of the compounds,pharmaceutical compositions containing one or more compounds of thegeneral formula I and especially their use as endothelin antagonists.

Endothelins (ET-1, ET-2, and ET-3) are 21-amino acid peptides producedand active in almost all tissues (Yanagisawa M et al.: Nature (1988)332:411). Endothelins are potent vasoconstrictors and importantmediators of cardiac, renal, endocrine and immune functions (McMillen MA et al.: J Am Coil Surg (1995) 180:621). They participate inbronchoconstriction and regulate neurotransmitter release, activation ofinflammatory cells, fibrosis, cell proliferation and celldifferentiation (Rubanyi G M et al.: Pharmacol Rev (1994) 46:328).

Two endothelin receptors have been cloned and characterized in mammals(ET_(A), ET_(B)) (Arai H et al.: Nature (1990) 348:730; Sakurai T etal.: Nature (1990) 348:732). The ET_(A) receptor is characterized byhigher affinity for ET-1 and ET-2 than for ET-3. It is predominant invascular smooth muscle cells and mediates vasoconstricting andproliferative responses (Ohlstein E H et al.: Drug Dev Res (1993)29:108). In contrast, the ET_(B) receptor has equivalent affinity forthe 3 endothelin isopeptides and binds the linear form of endothelin,tetra-ala-endothelin, and sarafotoxin S6C (Ogawa Y et al.: BBRC (1991)178:248). This receptor is located in the vascular endothelium andsmooth muscles, and is also particularly abundant in lung and brain. TheET_(B) receptor from endothelial cells mediates transient vasodilatorresponses to ET-1 and ET-3 through the release of nitric oxide and/orprostacyclin whereas the ET_(B) receptor from smooth muscle cells exertsvasoconstricting actions (Sumner M J et al.: Brit J Pharmacol (1992)107:858). ET_(A) and ET_(B) receptors are highly similar in structureand belong to the superfamily of G-protein coupled receptors.

A pathophysiological role has been suggested for ET-1 in view of itsincreased plasma and tissue levels in several disease states such ashypertension, sepsis, atherosclerosis, acute myocardial infarction,congestive heart failure, renal failure, migraine and asthma. As aconsequence, endothelin receptor antagonists have been studiedextensively as potential therapeutic agents. Endothelin receptorantagonists have demonstrated preclinical and/or clinical efficacy invarious diseases such as cerebral vasospasm following subarachnoidhemorrhage, heart failure, pulmonary and systemic hypertension,neurogenic inflammation, renal failure and myocardial infarction.

Today, no endothelin receptor antagonist is marketed yet, several are inclinical trials. However, these molecules possess a number of weaknessessuch as complex synthesis, low solubility, high molecular weight, poorpharmacokinetics, or safety problems (e.g. liver enzyme increases).

The inhibitory activity of the compounds of general formula I onendothelin receptors can be demonstrated using the test proceduresdescribed hereinafter:

For the evaluation of the potency and efficacy of the compounds of thegeneral formula I the following tests were used:

1) Inhibition of Endothelin Binding to Membranes from CHO Cells CarryingHuman ET Receptors

For competition binding studies, membranes of CHO cells expressing humanrecombinant ET_(A) or ET_(B) receptors were used. Microsomal membranesfrom recombinant CHO cells were prepared and the binding assay made aspreviously described (Breu V., et al, FEBS Lett 1993; 334:210).

The assay was performed in 200 uL 50 mM Tris/HCl buffer, pH 7.4,including 25 mM MnCl₂, 1 mM EDTA and 0.5% (w/v) BSA in polypropylenemicrotiter plates. Membranes containing 0.5 ug protein were incubatedfor 2 h at 20° C. with 8 pM [¹²⁵I ]ET-1 (4000 cpm) and increasingconcentrations of unlabelled antagonists. Maximum and minimum bindingwere estimated in samples without and with 100 nM ET-1, respectively.After 2 h, the membranes were filtered on filterplates containing GF/Cfilters (Unifilterplates from Canberra Packard S.A. Zürich,Switzerland). To each well, 50 uL of scintillation cocktail was added(MicroScint 20, Canberra Packard S.A. Zürich, Switzerland) and thefilter plates counted in a microplate counter (TopCount, CanberraPackard S.A. Zürich, Switzerland).

All the test compounds were dissolved, diluted and added in DMSO. Theassay was run in the presence of 2.5% DMSO which was found not tointerfere significantly with the binding. IC₅₀ was calculated as theconcentration of antagonist inhibiting 50% of the specific binding ofET-1. For reference compounds, the following IC₅₀ values were found:ET_(A) cells: 0.075 nM (n=8) for ET-1 and 118 nM (n=8) for ET-3; ET_(B)cells: 0.067 nM (n=8) for ET-1 and 0.092 nM (n=3) for ET-3 .

The IC₅₀ values obtained with compounds of general formula I are givenin Table 1.

TABLE 1 IC₅₀[nM] Compound of Example ET_(A) ET_(B) Example 1 1.8 569Example 2 25.4 1835 Example 3 46.3 722 Example 6 82.4 1351 Example 1328.7 3989 Example 4 273.4 8605 Example 11 18.53 264.2 Example 12 52.1532 Example 5 12.8 129.5 Example 14 4.75 841 Example 15 17.98 2129Example 16 62.2 1125 Example 21 14.67 749 Example 23 8.2 270 Example 2421.7 657 Example 27 11.5 193 Example 30 41.8 9075 Example 36 20 3392Example 40 6.2 629 Example 41 5.4 1781 Example 43 4.6 408 Example 4519.3 332 Example 46 41.7 541 Example 47 7.04 752 Example 48 10.6 832Example 49 27.2 4143 Example 50 30.99 6894 Example 51 4.56 173 Example52 7.5 1487 Example 53 21 1362 Example 54 14 183 Example 58 24 277Example 60 30 558 Example 62 58 4905 Example 65 17 2517 Example 67 7.8752 Example 69 6 1647 Example 70 16 258 Example 71 17 507 Example 72 92385 Example 73 7.6 4757 Example 74 7.8 3526 Example 75 17.6 >10000Example 80 19.7 2569 Example 83 27.5 7589 Example 85 3.8 238 Example 864.6 193 Example 87 3.9 439 Example 88 6 496 Example 89 4.6 1221 Example90 4.3 336 Example 92 20 7470 Example 95 33 8391 Example 101 30.7 8682Example 104 54 8336 Example 107 8.5 4645 Example 109 39 >10000 Example113 14.7 >10000 Example 114 18.4 3876 Example 116 24.9 >10000 Example117 7.9 4339 Example 118 9.8 1005 Example 119 55 735 Example 120 38.71630 Example 124 33.2 309 Example 125 6.7 2700 Example 126 9 3644Example 127 14.2 2755 Example 132 5.7 1660 Example 133 8.2 1770 Example134 6.3 4895 Example 138 4.4 1335 Example 139 9.8 1688 Example 140 12.51090 Example 144 10 3059 Example 145 9.1 2385 Example 146 7.8 3526Example 147 7.6 4757 Example 152 43.3 4822 Example 157 21.7 4505 Example158 12.1 1259 Example 159 7.3 2277 Example 160 12.9 757 Example 164 101564 Example 166 15 756 Example 173 4.2 976 Example 174 6.7 1010 Example175 4.7 499 Example 176 4.1 1079 Example 177 5.5 363 Example 178 5 671Example 179 9 699 Example 180 7.4 1027 Example 181 7.1 1977 Example 18216.7 1405 Example 193 2.6 537 Example 194 7.8 627 Example 195 6 293Example 196 4.7 427 Example 197 5 220 Example 198 7.9 595 Example 2022.4 349 Example 203 3.4 249 Example 204 3.3 138 Example 211 38 2638Example 214 39 3942 Example 222 41 506 Example 225 5.2 830 Example 22615.4 1547 Example 227 4.3 145 Example 228 14.5 3911 Example 230 12.3 937Example 232 10 290 Example 240 26 31262) Inhibition of Endothelin-Induced Contractions on Isolated Rat AorticRings (ET_(A) Receptors) and Rat Tracheal Rings (ET_(B) Receptors):

The functional inhibitory potency of the endothelin antagonists wasassessed by their inhibition of the contraction induced by endothelin-1on rat aortic rings (ET_(A) receptors) and of the contraction induced bysarafotoxin S6c on rat tracheal rings (ET_(B) receptors). Adult Wistarrats were anesthetized and exsanguinated. The thoracic aorta or tracheawere excised, dissected and cut in 3-5 mm rings. Theendothelium/epithelium was removed by gentle rubbing of the intimalsurface. Each ring was suspended in a 10 ml isolated organ bath filledwith Krebs-Henseleit solution (in mM; NaCl 115, KCl 4.7, MgSO₄ 1.2,KH₂PO₄ 1.5, NaHCO₃ 25, CaCl₂ 2.5, glucose 10) kept at 37° and gassedwith 95% O₂ and 5% CO₂. The rings were connected to force transducersand isometric tension was recorded (EMKA Technologies SA, Paris,France). The rings were stretched to a resting tension of 3 g (aorta) or2 g (trachea). Cumulative doses of ET-1 (aorta) or sarafotoxin S6c(trachea) were added after a 10 min incubation with the test compound orits vehicle. The functional inhibitory potency of the test compound wasassessed by calculating the concentration ratio, i.e. the shift to theright of the EC₅₀ induced by different concentrations of test compound.EC₅₀ is the concentration of endothelin needed to get a half-maximalcontraction, pA₂ is the negative logarithm of the antagonistconcentration which induces a two-fold shift in the EC₅₀ value. The pA₂values obtained with compounds of formula I are given in Table 2.

TABLE 2 pA₂ value Compound of Example ET_(A) ET_(B) Example 1 8.73 7.09Example 14 8.67 Example 15 7.57 Example 43 9.07 Example 67 9.5 Example80 8.35 5.21 Example 85 9.07 Example 92 7.91 Example 140 8.73 Example152 7.69 6.04 Example 173 8.83 7.1 Example 174 7.88 Example 193 8.6 6.9Example 194 7.5 6.5 Example 195 8.04 Example 196 7.68 Example 209 6.58Example 211 7.61 6.65

Because of their ability to inhibit the endothelin binding, thedescribed compounds can be used for treatment of diseases which areassociated with an increase in vasoconstriction, proliferation orinflammation due to endothelin. Examples of such diseases arehypertension, coronary diseases, cardiac insufficiency, renal andmyocardial ischemia, renal failure, cerebral ischemia, dementia,migraine, subarachnoidal hemorrhage, Raynaud's syndrome, portalhypertension and pulmonary hypertension. They can also be used foratherosclerosis, prevention of restenosis after balloon or stentangioplasty, inflammation, stomach and duodenal ulcer, cancer, prostatichypertrophy, erectile dysfunction, hearing loss, amaurosis, chronicbronchitis, asthma, gram negative septicemia, shock, sickle cell anemia,glomerulonephritis, renal colic, glaucoma, therapy and prophylaxis ofdiabetic complications, complications of vascular or cardiac surgery orafter organ transplantation, complications of cyclosporin treatment,pain as well as other diseases presently known to be related toendothelin.

The compounds can be administered orally, rectally, parenterally, e.g.by intravenous, intramuscular, subcutaneous, intrathecal or transdermaladministration or sublingually or as ophthalmic preparation oradministered as aerosol. Examples of applications are capsules, tablets,orally administered suspensions or solutions, suppositories, injections,eye-drops, ointments or aerosols/nebulizers.

Preferred applications are intravenous, intramuscular, or oraladministrations as well as eye drops. The dosage used depends upon thetype of the specific active ingredient, the age and the requirements ofthe patient and the kind of application. Generally, dosages of 0.1-50mg/kg body weight per day are considered. The preparations withcompounds can contain inert or as well pharmacodynamically activeexcipients. Tablets or granules, for example, could contain a number ofbinding agents, filling excipients, carrier substances or diluents.

The present invention relates to arylethene-sulfonamides of the generalformula I,

wherein

-   -   R¹ and R² represent aryl; heteroaryl;    -   R³ represents phenyl; mono-, di- or tri-substituted phenyl        substituted with lower alkyl, lower alkenyl, lower alkynyl,        phenyl, lower alkyloxy, amino, lower alkylamino, amino-lower        alkyl, trifluoromethyl, trifluoromethoxy, halogen, lower        alkylthio, hydroxy, hydroxy-lower alkyl, cyano, carboxyl, lower        alkanoyl, formyl; benzofuranyl; aryl; heteroaryl;    -   R⁴ represents hydrogen; halogen; trifluoromethyl; lower alkyl;        lower alkyl-amino; lower alkyloxy; lower alkyl-sulfono; lower        alkyl-sulfinyl; lower alkylthio; lower alkylthio-lower alkyl;        hydroxy-lower alkyl; lower alkyl-oxy-lower alkyl; hydroxy-lower        alkyl-oxy-lower alkyl; hydroxy-lower alkyl-amino; lower        alkyl-amino-lower alkyl; amino; di-lower alkyl-amino;        [N-(hydroxy-lower alkyl)-N-(lower alkyl)]-amino; aryl;        aryl-amino; aryl-lower alkyl-amino; aryl-thio; aryl-lower        alkyl-thio; aryloxy; aryl-lower alkyl-oxy; aryl-lower alkyl;        aryl-sulfinyl; heteroaryl; heteroaryl-oxy; heteroaryl-lower        alkyl-oxy; heteroaryl-amino; heteroaryl-lower alkyl-amino;        heteroaryl-thio; heteroaryl-lower alkyl-thio; heteroaryl-lower        alkyl; heteroaryl-sulfinyl; heterocyclyl; heterocyclyl-lower        alkyl-oxy; heterocyclyl-oxy; heterocyclyl-amino;        heterocyclyl-lower alkyl-amino; heterocyclyl-thio;        heterocyclyl-lower alkyl-thio; heterocyclyl-lower alkyl;        heterocyclyl-sulfinyl; cycloalkyl; cycloalkyl-oxy;        cycloalkyl-lower alkyl-oxy; cycloalkyl-amino; cycloalkyl-lower        alkyl-amino; cycloalkyl-thio; cycloalkyl-lower alkyl-thio;        cycloalkyl-lower alkyl; cycloalkyl-sulfinyl;    -   R⁵ and R⁶ represent hydrogen or lower alkyl and may be the same        or different;    -   X represents oxygen; sulfur; NH; CH₂ or a bond;    -   Y represents oxygen; sulfur or —NH—;    -   Z represents oxygen; sulfur, —NH— or a bond;    -   Q represents —(CH₂)_(n)—; —(CH₂)_(m)—C≡C—(CH₂)_(p)—, in case p        represents the whole number O, Z represents a bond;        —CH₂-cyclopropylen—CH₂—;    -   n represents the whole numbers 2, 3, 4, 5, 6;    -   m represents the whole numbers 1, 2 or 3;    -   p represents the whole numbers 0, 1, 2 or 3;        and pure diastereomers, mixtures of diastereomers,        diastereomeric racemates, mixtures of diastereomeric racemates        and the meso-forms and pharmaceutically acceptable salts        thereof.

In the definitions of the general formula I—if not otherwise stated—theexpression lower means straight and branched chain groups with one toseven carbon atoms, preferably 1 to 4 carbon atoms. Examples of loweralkyl and lower alkoxy groups are methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl, sec.-butyl, tert.-butyl, pentyl, hexyl, heptyl,methoxy, ethoxy, propoxy, butoxy, iso-butoxy, sec.-butoxy andtert.-butoxy. Lower alkylendioxy-groups are preferably methylen-dioxy,ethylen-dioxy, propylen-dioxy and butylen-dioxy groups. Examples oflower alkanoyl-groups are acetyl, propanoyl and butanoyl. Loweralkenylen means e.g. vinylen, propenylen and butenylen. Lower alkenyland lower alkynyl means groups like ethylen, propylen, butylen,2-methyl-propenyl, and ethinylen, propinylen, butinylen, pentinylen,2-methyl-pentinylen etc. Lower alkenyloxy means allyloxy, vinyloxy,propenyloxy and the like. The expression cycloalkyl means a saturatedcyclic hydrocarbon ring with 3 to 7 carbon atoms, e.g. cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, which may besubstituted with lower alkyl, hydroxy-lower alkyl, amino-lower alkyl,lower alkoxy-lower alkyl and lower alkenylen groups. The expressionheterocyclyl means saturated or unsaturated (but not aromatic ) four,five-, six- or seven-membered rings containing one or two nitrogen,oxygen or sulfur atoms which may be the same or different and whichrings may be adequatly substituted with lower alkyl, amino, nitro,hydroxy, lower alkoxy, e.g. piperidinyl, morpholinyl, thiomorpholinyl,piperazinyl, tetrahydropyranyl, dihydropyranyl, 1,4-dioxanyl,pyrrolidinyl, tetrahydrofuranyl, dihydropyrrolyl, dihydroimidazolyl,dihydropyrazolyl, pyrazolidinyl, 5-oxo-1,2,4-oxadiazolyl,5-oxo-1,2,4-thiadiazolyl, 5-thioxo-1,2,4-oxadiazolyl,2-oxo-1,2,3,5-oxathiadiazolyl etc. and substituted derivatives of suchrings with substituents as outlined above. The expression heteroarylmeans six-membered aromatic rings containing one to four nitrogen atoms,benzofused six-membered aromatic rings containing one to three nitrogenatoms, five-membered aromatic rings containing one oxygen or onenitrogen or one sulfur atom, benzo- fused five-membered aromatic ringscontaining one oxygen or one nitrogen or one sulfur atom, five memberedaromatic rings containing an oxygen and nitrogen atom and benzo fusedderivatives thereof, five membred aromatic rings containing a sulfur anda nitrogen atom and benzo fused derivatives thereof, five-memberedaromatic rings containing two nitrogen atoms and benzo fused derivativesthereof, five membered aromatic rings containing three nitrogen atomsand benzo fused derivatives thereof or the tetrazolyl ring; e.g.furanyl, thienyl, pyrrolyl, pyridinyl, pyrimidinyl, indolyl, quinolinyl,isoquinolinyl, imidazolyl, triazinyl, thiazinyl, thiazolyl,isothiazolyl, pyridazinyl, oxazolyl, isoxazolyl, triazinyl, thiazinyl,thiazolyl, isothiazolyl, pyridazinyl, oxazolyl, isoxazolyl etc. wherebysuch rings may be substituted with lower alkyl, lower alkenyl, amino,amino-lower alkyl, halogen, hydroxy, lower alkoxy, trifluoromethoxy,trifluoromethyl, carboxyl, carboxamidyl, thioamidyl, amidinyl, loweralkyl-methanoylate, cyano, hydroxy-lower alkyl, lower alkyl-oxy-loweralkyl or another heteroaryl- (preferrably tetrazolyl) orheterocyclyl-ring (preferrably 5-oxo-1,2,4-oxadiazolyl,5-oxo-1,2,4-triazolyl, 5-oxo-1,2,4-thiadiazolyl,5-thioxo-1,2,4-oxadiazolyl or 2-oxo-1,2,3,5-oxathiadiazolyl). Theexpression aryl represents unsubstituted as well as mono-, di- ortri-substituted aromatic rings with 6 to 10 carbon atoms like phenyl ornaphthyl rings which may be substituted with aryl, halogen, hydroxy,lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy, loweralkenyloxy, lower alkynyl-lower alkyl-oxy, lower alkenylen, loweralkylenoxy, lower alkylenoxy or lower alkylendioxy forming with thephenyl ring a five- or six-membered ring, hydroxy-lower alkyl,hydroxy-lower alkenyl, hydroxy-lower alkyl-lower alkynyl, loweralkyloxy-lower alkyl, lower alkyloxy-lower alkyloxy, trifluoromethyl,trifluoromethoxy, cycloalkyl, hydroxy-cycloalkyl, heterocyclyl,heteroaryl.

In the compounds of the present invention, there are geometrical isomerssuch as cis- and trans-compounds [or (E)- and (Z)-compounds] possibledue to double bonds present in the compounds covered by general formulaI. The present invention covers each of the separated isomers [(E)- or(Z)-compound], as well as mixtures of both isomers in any ratio. In thepresent invention the compounds according to general formula I, in whichthe groups R⁵ and R⁶ are in trans-configuration are especiallypreferred.

Especially preferred compounds are compounds of general formula Iwherein R³ represents phenyl or mono-substituted phenyl substituted withlower alkyloxy, especially methoxy and X represents oxygen.

A second group of especially preferred compounds of general formula Iare the compounds wherein R³ represents phenyl or mono-substitutedphenyl substituted with lower alkoxy, especially methoxy and X, Y and Zrepresent oxygen.

A third group of especially preferred compounds of general formula I arethe compounds wherein R³ represents phenyl or mono-substituted phenylsubstituted with lower alkoxy, especially methoxy, X, Y and Z representoxygen and Q represents —(CH₂)_(n)— with n=2 or 3.

A fourth group of especially preferred compounds of general formula Iare the compounds wherein R³ represents di-substituted phenylsubstituted with one halogen and one lower alkoxy-group, especially onemethoxy-group, X, Y and Z represent oxygen and Q represents—(CH₂)_(n)—with n=2 or 3.

A fifth group of especially preferred compounds of general formula I arethe compounds wherein R³ represents or mono- or di-substituted phenylsubstituted with a chlorine atom and/or lower alkoxy, especiallymethoxy, X, Y and Z represent oxygen, Q represents —(CH₂)_(n)— with n=2or 3 and R² represents heteroaryl.

The expression pharmaceutically acceptable salts encompasses eithersalts with inorganic acids or organic acids like hydrohalogenic acids,e.g. hydrochloric or hydrobromic acid; sulfuric acid, phosphoric acid,nitric acid, citric acid, formic acid, acetic acid, maleic acid,tartaric acid, methylsulfonic acid, p-toluolsulfonic acid and the likeor in case the compound of formula I is acidic in nature with aninorganic base like an alkali or earth alkali base, e.g. sodiumhydroxide, potassium hydroxide, calcium hydroxide etc.

The compounds of the general formula I might have one or more asymmetriccarbon atoms and may be prepared in form of optically pure enantiomersor diastereomers, mixtures of enantiomers or diastereomers,diastereomeric racemates, mixtures of diastereomeric racemates and alsoin the meso-form. The present invention encompasses all these forms.Mixtures may be separated in a manner known per se, i.e. by columnchromatography, thin layer chromatography, HPLC, crystallization etc.

Because of their ability to inhibit the endothelin binding, thedescribed compounds of the general formula I and their pharmaceuticallyacceptable salts may be used for treatment of diseases which areassociated with an increase in vasoconstriction, proliferation orinflammation due to endothelin. Examples of such diseases arehypertension, coronary diseases, cardiac insufficiency, renal andmyocardial ischemia, renal failure, cerebral ischemia, dementia,migraine, subarachnoidal hemorrhage, Raynaud's syndrome, portalhypertension and pulmonary hypertension. They can also be used fortreatment of atherosclerosis, prevention of restenosis after balloon orstent angioplasty, inflammation, stomach and duodenal ulcer, cancer,prostatic hypertrophy, erectile dysfunction, hearing loss, amaurosis,chronic bronchitis, asthma, gram negative septicemia, shock, sickle cellanemia, glomerulonephritis, renal colic, glaucoma, therapy andprophylaxis of diabetic complications, complications of vascular orcardiac surgery or after organ transplantation, complications ofcyclosporin treatment, pain, as well as other diseases presently knownto be related to endothelin.

These compositions may be administered in enteral or oral form e.g. astablets, dragees, gelatine capsules, emulsions, solutions orsuspensions, in nasal form like sprays or rectally in form ofsuppositories. These compounds may also be administered inintramuscular, parenteral or intravenous form, e.g. in form ofinjectable solutions.

These pharmaceutical compositions may contain the compounds of formula Ias well as their pharmaceutically acceptable salts in combination withinorganic and/or organic excipients which are usual in thepharmaceutical industry like lactose, maize or derivatives thereof,talcum, stearinic acid or salts of these materials.

For gelatine capsules vegetable oils, waxes, fats, liquid or half-liquidpolyols etc. may be used. For the preparation of solutions and sirupse.g. water, polyols, saccharose, glucose etc. are used. Injectables areprepared by using e.g. water, polyols, alcohols, glycerin, vegetableoils, lecithin, liposomes etc. Suppositories are prepared by usingnatural or hydrogenated oils, waxes, fatty acids (fats), liquid orhalf-liquid polyols etc.

The compositions may contain in addition preservatives, stabilisationimproving substances, viscosity improving or regulating substances,solubility improving substances, sweeteners, dyes, taste improvingcompounds, salts to change the osmotic pressure, buffer, anti-oxidantsetc.

The compounds of formula I may also be used in combination with one ormore other therapeutically useful substances e.g. α- and β-blockers likephentolamine, phenoxybenzamine, atenolol, propranolol, timolol,metoprolol, carteolol etc.; Vasodilators like hydralazine, minoxidil,diazoxide, flosequinan etc.; Calcium-antagonists like diltiazem,nicardipine, nimodipine, verapamil, nifedipine etc.; ACE-inhibitors likecilazapril, captopril, enalapril, lisinopril etc.; Potassium activatorslike pinacidil etc.; Angiotensin II antagonists; Diuretics likehydrochlorothiazide, chlorothiazide, acetolamide, bumetanide,furosemide, metolazone, chlortalidone etc.; Sympatholitics likemethyldopa, clonidine, guanabenz, reserpine etc.; and other therapeuticswhich serve to treat high blood pressure or any cardiac disorders.

The dosage may vary within wide limits but should be adapted to thespecific situation. In general the dosage given daily in oral formshould be between about 3 mg and about 3 g, preferably between about 10mg and about 1 g, especially preferred between 5 mg and 300 mg, peradult with a body weight of about 70 kg. The dosage should beadministered preferably in 1 to 3 doses per day which are of equalweight. As usual children should receive lower doses which are adaptedto body weight and age.

Preferred compounds are compounds of formula II

wherein R¹, R², R³, R⁴, R⁵, R⁶, Y, Q and Z are as defined in generalformula I above,and pharmaceutically acceptable salts of compounds of formula II.

Also preferred are compounds of formula III

wherein R¹, R², R⁴, R⁵, R⁶, Y, Q and Z are as defined in general formulaI above and T represents a chlorine-, a bromine- or a hydrogen-atom or amethyl group or a methoxy group, and pharmaceutically acceptable saltsof compounds of formula III.

Also preferred are compounds of formula IV

wherein R¹, R², R³, R⁴ and Q are as defined in general formula I above,and pharmaceutically acceptable salts of compounds of formula IV.

Another especially preferred group of compounds are compounds of formulaV

wherein R¹ and R² are as defined in general formula I above, and Trepresents a chlorine-, a bromine- or a hydrogen-atom or a methyl groupor a methoxy group, and pharmaceutically acceptable salts thereof.

Especially preferred compounds among the group of compounds of formula Vare those wherein R² represents heteroaryl.

Preferred compounds are:

-   2-Phenyl-ethenesulfonic acid    [6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]-5-p-tolyl-pyrimidin-4-yl]-amide;-   2-Phenyl-ethenesulfonic acid    {5-(4-bromo-phenyl)-6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]-pyrimidin-4-yl}-amide;-   2-Phenyl-ethenesulfonic acid    {6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]-5-phenyl-pyrimidin-4-yl}-amide-   2-Phenyl-ethenesulfonic acid    {6-[2-(5-chloro-pyrimidin-2-yloxy)-ethoxy]-5-p-tolyl-pyrimidin-4-yl}-amide;-   2-Phenyl-ethenesulfonic acid    {6-[2-(4-bromo-phenoxy)-ethoxy]-5-p-tolyl-pyrimidin-4-yl}-amide;-   2-Thiophen-3-yl-ethenesulfonic acid    {6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]-5-p-tolyl-pyrimidin-4yl}-amide;-   2-Thiophen-2-yl-ethenesulfonic acid    {6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]-5-p-tolyl-pyrimidin-4-yl}-amide;-   2-Thiophen-2-yl-ethenesulfonic acid    {6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]-5-p-tolyl-[2,2′]bipyrimidinyl-4-yl}-amide;-   2-Phenyl-ethenesulfonic acid    {6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]-5-p-tolyl-[2,2′]bipyrimidinyl-4-yl}-amide;-   2-Phenyl-ethenesulfonic acid    [6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]-5-(2-methoxy-phenoxy)-pyrimidin-4-yl]-amide;-   2-Phenyl-ethenesulfonic acid    [6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]-5-(3-methoxy-phenoxy)-pyrimidin-4-yl]-amide;-   2-Phenyl-ethenesulfonic acid    [6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]-5-(2-methoxy-phenoxy)-2-pyrazin-2-yl-pyrimidin-4-yl]-amide;-   2-Phenyl-ethenesulfonic acid    [6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]-5-(2-methoxy-phenoxy)-2-morpholin-4-yl-pyrimidin-4yl-pyrimidin-4yl]-amide;-   2-Phenyl-ethenesulfonic acid    {5-(2-methoxy-phenoxy)-2-morpholin-4-yl-6-[2-(5-trifluoromethyl-pyrimidin-2-yloxy)-ethoxy]-prrimidin-4yl}-amide;-   2-Phenyl-ethenesulfonic acid    {5-(2-methoxy-phenoxy)-6-[2-(pyrimidin-2-yloxy)-ethoxy]-[2,2]bipyrimidinyl-4-yl}-amide;-   2-Thiophen-2-yl-ethenesulfonic acid    [6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]-5-(2-methoxy-phenoxy)-[2,2′]bipyrimidinyl-4yl]-amide;-   2-Thiophen-2-yl-ethenesulfonic acid    [6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]-5-(2-methoxy-[phenoxy)-2-pyridin-4-yl-pyrimidin-4-yl]-amide;-   2-Phenyl-ethenesulfonic acid    [6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]-5-(2-chloro-5-methoxy-phenoxy)-pyrimidin-4-yl]-amide;    and pharmaceutically acceptable salts thereof.    Especially Preferred Compounds Are:-   2-Phenyl-ethenesulfonic acid    [6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]-5-(4-chloro-phenyl)-pyrimidin-4-yl]-amide;-   2-Phenyl-ethenesulfonic acid    {6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]-2-pyridin-4-yl-5-p-tolyl-pyrimidin-4-yl}-amide;    and pharmaceutically acceptable salts thereof.

Compounds of the general formula I of the present invention can beprepared according to the general sequence of reactions outlined below.For simplicity and clarity reasons sometimes only parts of the syntheticpossibilities which lead to compounds of general formula I aredescribed. The literature references given in brackets [ ] are set forthat the end of this paragraph.

Possibility A

The desired compounds of general formula I can be prepared by reacting acompound of the formula 1:

wherein G¹ is a reactive residue, preferentially a chloro atom, and theother symbols are as defined in general formula I above, with a compoundof the formula 2:

wherein the symbols are the same as defined in general formula I above,or a salt thereof.Possibility B

The compounds of general formula I may also be prepared by reacting acompound of formula 3:

wherein the symbols are the same as defined in general formula I above,or a salt thereof, with a compound of the formula 4;

wherein G² is a reactive residue, preferentially a halogen atom, and theother symbol is the same as defined in general formula I above.Possibility C

The compounds of general formula I may also be prepared by reacting acompound of the formula 5:

Wherein G³ is a lower alkylsulfonyl group or a phenylsulfonyl group or ahalogen atom, and the other symbols are the same as described in generalformula I above, or a salt thereof, with a compound of the formula 6:

wherein R⁴ is the same as defined in general formula I above, or a saltthereof.

For possibilities A to C see also [5]

The amidines 8 were synthesized applying standard methodology [1] byreaction of the appropriate nitrile 7 either with sodium methylate inmethanol followed by addition of ammonium chloride or by reaction withlithium hexamethyldisilazane followed by addition of hydrochloric acidin i-propanol. The 2-substituted malonic esters 10 were preparedaccording to published procedures [2] by reacting dimethylchloromalonate(9) with the appropriate alcohol 11 in acetone and potassium carbonateas base. The compounds 10 were dissolved in methanol and sodiummethylate was added and stirring was continued for about 30 min followedby the addition of an amidine derivative 8. Stirring at ambienttemperature was continued for another 8 h. After acidic work up the4,6-dihydroxypyrimidines 12 could be isolated in yields of 70 to 90%[2]. Compounds 12 or the tautomeric form thereof were transformed intothe dichloro derivatives 13 with phosphorous oxychloride in the presenceof N,N-dimethylaniline at elevated temperatures (60-120° C.) in yieldsof 40 to 75% [3]. In some cases better yields were obtained by additionof PCI₅ or benzyl-triethylammoniumchloride. The dichlorides 13 werereacted with an excess of the appropriate sulfonamide potassium salt 15(prepared according to standard methodology from the sulfochlorides 14)in DMSO at room temperature to give the pyrimidines 16 in yields of 70to 90% either after recrystallization from ethyl acetate/diethylether orchromatography through silica gel with ethyl acetate/heptane. Thepyrimidine derivatives 16 are the central intermediates which can betransformed to the desired final products of general formula I either byapplying procedures outlined under Possibility A or they can betransformed to the derivatives 18 by reaction with a di-hydroxy-compoundrepresented by formula 17 in the presence of a base like sodium hydridein a solvent like THF at 50-80° C. and then transformed to finalcompounds according to the general formula I by applying proceduresoutlined under Possibility B above.

For further experimental descriptions see [1], [2], [3], [6].

The synthesis of compounds with X, Y or Z being another group thanoxygen, can be carried out in analogous procedures.

For further experimental descriptions see [1], [2], [3], [5], [6]. Forthe substitution of the sulfono-group, see especially [5]

The synthesis of compounds with X, Y or Z being another group thanoxygen, can be carried out in analogous procedures.

In the schemes 1 to 3 the symbols represent the same as defined ingeneral formula I above.

According to procedures described in the literature [11]-[13] theheteroaryl ethenylsufonamide derivatives 32 to 34 were prepared. The keystep in this sequence is the palladium catalyzed coupling ofvinylsulfonamide with the respective heteroaryl bromide. (In principleit is also possible to prepare the aryl ethenylsulfonamides via thisprocedure)

According to procedures described in the literature [14-19], thesubstituted aryl ethenyl sulfonamides 35 to 38 were prepared. Otherderivatives could be prepared from the respective styrene precursors.

-   [1] W. Göhring, J. Schildknecht, M. Federspiel; Chimia, 1996, 50,    538-543.-   [2] W. Neidhart, V. Breu, D. Bur, K. Burri, M. Clozel, G. Hirth, M.    Müller, H. P. Wessel, H. Ramuz; Chimia, 1996, 50, 519-524 and    references cited there.-   [3] W. Neidhart, V. Breu, K. Burri, M. Clozel, G. Hirth, U.    Klinkhammer, T. Giller, H. Ramuz; Bioorg. Med. Chem. Lett., 1997, 7,    2223-2228. R. A. Nugent, S. T. Schlachter, M. J. Murphy, G. J.    Cleek, T. J. Poel, D. G. Whishka, D. R. Graber, Y. Yagi, B. J.    Keiser, R. A. Olmsted, L. A. Kopta, S. M. Swaney, S. M. Poppe, J.    Morris, W. G. Tarpley, R. C. Thomas; J. Med. Chem., 1998, 41,    3793-3803.-   [4] J. March; Advanced Organic Chemistry, 4^(th) Ed., 1994, p. 499    and references cited there.-   [5] EP 0 743 307 A1; EP 0 658 548 B1; EP 0 959 072 A1 (Tanabe    Seiyaku)-   [6] EP 0 633 259 B1; EP 0 526 708 A1; WO 96/19459 (F.    Hoffmann-LaRoche)-   [7] for the Synthesis of 5-membered heterocycles see: Y. Kohara et    al; J. Med. Chem., 1996, 39, 5228-5235 and references cited there.-   [8] EP 0 882 719 A1 (Yamanouchi Pharmaceutical Co., Ltd).-   [9] WO 00/52007 (F. Hoffmann-LaRoche AG).-   [10] WO 00/42035 (F. Hoffmann-LaRoche AG).-   [11] ????; Bull. Soc. Chim. Fr.; 1981, 71.-   [12] ????; J. Org. Chem.; 1958, 23, 729.-   [13] ????; Bull. Chem. Soc. Jpn.; 1991, 64, 1431.-   [14] M. V. Ramana Reddy et al.; Phosphorous, Sulfur and Silicon;    1990, 53, 285-290.-   [15] S. S. Arogba; Organic Preparations and Procedures Int., 1991,    23(5), 639-643.-   [16] D. Bhaskar Reddy et al.; Phosphorous, Sulfur and Silicon; 1993,    84, 63-71.-   [17] M. Kameyama et al.; Bull. Chem. Soc. Jpn.; 1988, 61, 1231-1235.-   [18] B. M. Culbertson et al.; J. Chem. Soc. (C), 1968, 992-993.-   [19] D. Bhaskar Reddy et al.; Indian J. Chem.; 1995, 34B, 816-822.-   [20] J. M. Fox, X. Huang, A. Chieffi, S. L. Buchwald; J. Am. Chem.    Soc.; 2000, 122, 1360-1370.

REFERENTIAL EXAMPLES Synthesis of Precursors

The following compounds were prepared according to the proceduredescribed above and shown in Schemes 1 to 3. All compounds werecharacterized by 1 H-NMR (300 MHz) and occasionally by 13C-NMR (75 MHz)(Varian Oxford,) 300 MHz; chemical shifts are given in ppm relative tothe solvent used; multiplicities: s=singlet, d=doublet, t=triplet;m=multiplet), by LC-MS (Waters Micromass; ZMD-platform with ESI-probewith Alliance 2790 HT; Colum: 2×30 mm, Gromsil ODS4, 3 μm, 120 A;Gradient: 0-100% acetonitril in water, 6 min, with 0.05% formic acid,flow: 0.45 ml/min; t_(R) is given in min.), by TLC (TLC-plates fromMerck, Silica gel 60 F₂₅₄) and occasionally by melting point.

The following Referential Examples illustrate the invention but do notat all limit the scope thereof. All temperatures are stated in ° C.

Referential Example 1

a) To a mixture of 1,2-dimethoxyethan (15 ml) and ethyleneglycol (40 ml)was added sodium (298 mg) in small portions. The mixture was stirreduntil the sodium was completely dissolved. Then DMF (15 ml), followed by2-phenyl-ethenesulfonic acid(6-chloro-5-p-tolyl-pyrimidin-4-yl)-amide(1.0 g) was added. Stirring was continued for 4 days at 100° C. Themixture was evaporated and water (150 ml) was added to the residuefollowed by addition of acetic acid (1.0 ml). The precipitate wasfiltered off, washed with water and dried. The crude material waspurified by chromatography over silicagel with EtOAc/methanol/aqueousammonia (25%)=4/1/0.5 to give 2-phenyl-ethenesulfonicacid[6-(2-hydroxy-ethoxy)-5-p-tolyl-pyrimidin-4-yl]-amide (500 mg).t_(R)=4.54 (LC); M⁺=412.38 (ES+).

b) To 4,6-dichloro-5-p-tolyl-pyrimidine (2.0 g) disolved in DMSO (35 ml)was added di-isopropyl-ethyl-amine (1.46 ml) followed by2-phenyl-ethenesulfonamide potassium salt (2.78 g). The mixture wasstirred for 48 h at rt then poured onto water (500 ml) and diethylether(250 ml) was added and the solution was stirred for 30 minutes. Thelayers were separated and the water layer was acidified with acetic acid(2.0 ml) and cooled to 0° C. for 1 h. The precipitated product wasfiltered off and washed with water and diethylether and dried to give2-phenyl-ethenesulfonic acid(6-chloro-5-p-tolyl-pyrimidin-4-yl)-amide(2.02 g). t_(R)=5.32 (LC); M⁺=386.23 (ES+); M⁻=384.22 (ES−).

c) To 2-phenyl-ethenesulfonylchloride (10 g, commercially available fromAldrich) in THF (115 ml) was slowly added aqueous ammonia (25%) at 0° C.followed by stirring at rt for 30 min. The solvent was evaporated, theresidue dissolved in EtOAc and washed with water (3×). The organic layerwas dried over sodium sulfate, filtered and the solvent was evaporated.The residue was taken up in methanol (55 ml) and potassiumtert.-butoxide (4.88 g) was added in portions. Stirring was continuedfor 30 min, the solvent was evaporated and the residue was dried to give2-phenyl-ethenesulfonamide potassium salt (9.65 g). 1H-NMR (d6-DMSO):7.7(m, 2H); 7.4(m, 3H); 7.3(d, 1 H); 7.2(d, 1H); 7.05(s, 2H, NH₂).

d) 5-p-tolyl-pyrimidine-4,6-diol (17.2 g) was dissolved in phosphorusoxy chloride (250 ml) and N,N-dimethylaniline (25 ml) was added. Themixture was stirred at 70° C. for 16 h, then concentrated in vacuo. Theresidue was poured onto ice-water and extracted with diethylether (3×).The combined organic extracts were washed with 1N hydrochloric acid andwith saturated sodium chloride solution, dried over magnesium sulfate,filtered and the filtrate was evaporated. The crude brown material wasrecrystallized from i-propanol to give 4,6-dichloro-5-p-tolyl-pyrimidine(13.5 g). 1H-NMR (CDCl₃): 8.78(s, 1H); 7.35(d, 2H); 7.20(d, 2H); 2.41(s, 3H).

e) Sodium methylate (17 g) was dissolved in methanol (600 ml) at 0° C.2-p-Tolyl-malonic acid diethyl ester (24.5 ml, commercially availablefrom Aldrich), dissolved in 150 ml methanol, was added within 30 min.Stirring was continued for 1 h while slowly warming the mixture to rt.Formamidine hydrochloride (9.9 g, commercially available from Fluka) wasadded and stirring was continued for 16 h. The solvent was evaporatedand 2 M hydrochloric acid (200 ml) was added to the residue followed byslow addition of 10 M sodium hydroxide to adjust the pH to 5. Theprecipitated product was filtered off and washed subsequently with waterand diethylether and dried to give 5-p-tolyl-pyrimidine-4,6-diol (17.7g). 1H-NMR (d6-DMSO): 8.0(s, 1H); 7.4(d, 2H); 7.1(d, 2H); 2.25(s, 3H).

Referential Example 2

According to the procedure described in Referential Example 1a)2-phenyl-ethenesulfonic acid[6-(3-hydroxy-propoxy)-5-p-tolyl-pyrimidin-4-yl]-amide was prepared.t_(R)=4.58 (LC); [M−H]⁺=424.10 (ES−).

Referential Example 3

According to the procedure described in Referential Example 1a)2-phenyl-ethenesulfonic acid[6-(4-hydroxy-butoxy)-5-p-tolyl-pyrimidin-4-yl]-amide was prepared.t_(R)=4.66 (LC); [M+H]⁺=437.99 (ES+).

Referential Example 4

a) According to the procedure described in Referential Example 1a)2-Thiophen-2-yl-ethenesulfonic acid[6-(2-hydroxy-ethoxy)-5-p-tolyl-pyrimidin-4-yl]-amide was prepared.t_(R)=4.36 (LC); [M+H]⁺=418.15 (ES+).

b) According to the procedure described in Referential Example 1b),2-thiophen-2-yl-ethenesulfonic acid(6-chloro-5-p-tolyl-pyrimidin-4-yl)-amide was prepared from4,6-dichloro-5-p-tolyl-pyrimidine and thiophen-2-yl-ethenesulfonic acidamide potassium salt. t_(R)=5.05 (LC); [M+H]⁺=392.11 (ES+).

2-Thiophen-2-yl-ethenesulfonic acid amide was prepared according toprocedures described in the literature [11], [12], [13].

Referential Example 5

a) According to the procedure described in Referential Example 1a),2-thiophen-2-yl-ethenesulfonic acid[6-(2-hydroxy-ethoxy)-5-p-tolyl-[2,2′]bipyrimidinyl-4-yl]-amide wasprepared. t_(R)=4.39 (LC); [M+H]⁺=496.16 (ES+).

b) According to the procedure described in Referential Example 1b,2-thiophen-2-yl-ethenesulfonic acid(6-chloro-5-p-tolyl-[2,2′]bipyrimidinyl-4-yl)-amide was prepared from4,6-dichloro-5-p-tolyl-[2,2′]bipyrimidinyl and2-thiophen-2-yl-ethenesulfonic acid amide potassium salt. t_(R)=4.84(LC); [M+H]⁺=470.00.

c) Accoridng to the procedure described in Referential Example 1c),4,6-dichloro-5-p-tolyl-[2,2′]bipyrimidinyl was prepared. t^(R)=4.42(LC); [M+H]⁺=317.08.

d) According to the procedure described in Referential Example 1d),5-p-tolyl-[2,2′]bipyrimidinyl-4,6-diol was prepared. t_(R)=3.38 (LC);[M+H]⁺=281.08.

Referential Example 6

According to procedures described in the synthetic sequence inReferential Example 1a-e, by using isonicotinamidine hydrochlorideinstead of formamidine hydrochloride in the first step of the synthesis,2-phenyl-ethenesulfonic acid[6-(2-hydroxy-ethoxy)-2-pyridin-4-yl-5-p-tolyl-pyrimidin-4-yl]-amide wasprepared. t_(R)=4.36 (LC); [M+H]⁺=489.39.

Referential Example 7

According to procedures described in the synthetic sequence inReferential Example 1a-e, by using cyclopropylformamidine hydrochlorideinstead of formamidine hydrochloride in the first step of the synthesis,2-phenyl-ethenesulfonicacid-[2-cyclopropyl-6-(2-hydroxy-ethoxy)-5-p-tolyl-pyrimidin-4-yl]-amidewas prepared. t_(R)=5.12 (LC); [M−H]⁺=450.12 (ES−).

Referential Example 8

According to procedures described in the synthetic sequence inReferential Example 1a-e, by using morpholinoformamidine hydrochlorideinstead of formamidine hydrochloride in the first step of the synthesis,2-phenyl-ethenesulfonic acid[6-(2-hydroxy-ethoxy)-2-morpholin-4-yl-5-p-tolyl-pyrimidin-4-yl]-amidewas prepared. t_(R)=4.91 (LC); [M+H]⁺=497.46 (ES+).

Referential Example 9

According to procedures described in the synthetic sequence inReferential Example 1a-e, by using pyrazinylformamidine hydrochlorideinstead of formamidine hydrochloride in the first step of the synthesis,2-phenyl-ethenesulfonic acid[6-(2-hydroxy-ethoxy)-2-pyrazin-2-yl-5-p-tolyl-pyrimidin-4-yl]-amide wasprepared. t_(R)=4.59 (LC); [M+H]⁺=490.31 (ES+).

Referential Example 10

According to procedures described in the synthetic sequence inReferential Example 1 a-e, by using pyrimidin-2-yl-formamidinehydrochloride instead of formamidine hydrochloride in the first step ofthe synthesis, 2-phenyl-ethenesulfonic acid[6-(2-hydroxy-ethoxy)-5-p-tolyl-[2,2′]bipyrimidinyl-4-yl]-amide wasprepared. t_(R)=4.51 (LC); [M+H]⁺=490.34 (ES+).

Referential Example 11

a) 6.20 g of 2-phenyl-ethenesulfonic acid[6-chloro-5-(4-chloro-phenyl)-pyrimidin-4-yl]-amide was added to asolution of 7.65 g of potassium-tert.-butylate in 100 ml of ethyleneglycol. The resulting solution was heated to 110° C. and stirred for 17h. The ethylene glycol was evaporated under high vacuum and theremaining residue was treated with 250 ml of cold water. The suspensionwas acidified by adding 10 g of citric acid monohydrate and stirred at0° C. for 15 min. The precipitate was collected, washed with water anddried to give 6.71 g of 2-phenyl-ethenesulfonic acid[5-(4-chloro-phenyl)-6-(2-hydroxy-ethoxy)-pyrimidin-4-yl]-amide as awhite powder. LC-MS: t_(R)=4.55 min, [M+H]⁺=432.00 (ES+), [M−H]⁻=429.98(ES−).

b) A solution of 6.50 g of 4,6-dichloro-5-(4-chlorophenyl)-pyrimidineand 9.43 g of 2-phenyl-ethenesulfonamide potassium salt (ReferentialExample 1c) in 50 ml of DMSO and 4.4 ml of diisopropyl-ethylamine wasstirred at rt for 65 h. The mixture was diluted with 500 ml of water and250 ml of diethyl ether and was vigorously stirred for 15 min. Thesuspension was acidified by adding 8.5 g of citric acid monohydrate andstirring was continued at 5° C. for 30 min. The precipitate wascollected and washed with water. The crude product was crystallised from2-propanol at 2-3° C. The crystals were collected, washed with cold2-propanol and dried to give 6.23 g of 2-phenyl-ethenesulfonic acid[6-chloro-5-(4-chloro-phenyl)-pyrimidin-4-yl]-amide as a white powder.LC-MS: t_(R)=5.24 min, [M+H]⁺=405.89 (ES+), [M−H]⁻=403.92 (ES−).

c) To a suspension of 16.44 g of 5-(4-chlorophenyl)-pyrimidine-4,6-diolin 165 ml of POCl₃ was carefully added 16.5 ml of N,N-dimethylaniline.The mixture was refluxed for 1.5 h. The dark green solution wasevaporated and the residue was poured onto ice/water. The suspension wasdiluted with 200 ml 2 N HCl and water to about 1000 ml and stirred at 2°C. for 1 h. The precipitate was collected, washed with water and driedto give 18.66 g of 4,6-dichloro-5-(4-chlorophenyl)-pyrimidine as aslightly green powder.

d) A solution of 18.90 g of 2-(4-chloro-phenyl)-malonic acid dimethylester in 200 ml of methanol was added dropwise at 0° C. to a solution of14.60 g sodium methylate in 150 ml of methanol. The mixture was stirredfor 1 h at 0° C. before 7.66 g of formamidine hydrochloride was added.The suspension was stirred at rt for 20 h. The solvent was removed andthe residue was suspended in 200 ml 2 N aq. HCl. The pH of thesuspension was carfully adjusted to 4-5 by adding 20 ml of 10 M NaOH,stirring was continued for 30 min. The white precipitate was collected,washed with water and diethyl ether and dried to give 16.44 g of5-(4-chlorophenyl)-pyrimidine-4,6-diol as a white powder. LC-MS:t_(R)=2.75 min, [M+H]⁺=222.96 (ES+), [M−H]⁻=220.92 (ES−).

e) At 35° C. a solution of 52 g of 4-chlorophenylacetic acid methylester in 170 ml of THF was carefully added over a period of 70 min to asuspension of 15.6 g NaH in 550 ml of dry THF. Stirring was continuedfor 40 min without heating and the temperature dropped to 29° C. Theevolution of gas had stopped before 94.8 ml of dimethylcarbonate wasadded dropwise while the temperature of the mixture was maintained at25-28° C. After the evolution of gas had ceased, the mixture was dilutedwith 200 ml of THF and stirring was continued for 72 h at rt.

The mixture was carefully acidified with aq. HCl before bulk of the THFwas removed in vacuo. The residue was dissolved in 1200 ml of diethylether, washed three times with 1 N aq. HCl and once with brine, driedover MgSO₄ and evaporated. The residue formed was collected, washed withdiethyl ether and dried to give 42 g of 2-(4-chloro-phenyl)-malonic aciddimethyl ester as white crystals.

Referential Example 12

According to the procedures described in Referential Example 11a-e, byusing 4-bromophenylacetic acid methyl ester as the initial startingmaterial, 2-phenyl-ethenesulfonic acid[5-(4-bromo-phenyl)-6-(2-hydroxy-ethoxy)-pyrimidin-4-yl]-amide wasobtained. LC-MS: t_(R)=4.57 min, [M+H]⁺=478.05 (ES+).

Referential Example 13

According to the procedures described in Referential Example 11a-e, byusing 4-methoxyphenylacetic acid methyl ester as the initial startingmaterial, 2-phenyl-ethenesulfonic acid[5-(4-methoxy-phenyl)-6-(2-hydroxy-ethoxy)-pyrimidin-4-yl]-amide wasobtained. LC-MS: t_(R)=4.29 min, [M+H]⁺=428.20 (ES+).

Referential Example 14

According to the procedures described in Referential Example 11a-d, byusing diethyl phenylmalonate as the initial starting material,2-phenyl-ethenesulfonic acid[5-phenyl-6-(2-hydroxy-ethoxy)-pyrimidin-4-yl]-amide was obtained.LC-MS: t_(R)=4.32 min, [M+H]⁺=398.17 (ES+).

Referential Example 15

According to the procedures described in Referential Example 11a-d, byusing 4-ethylphenylmalonic acid dimethylester, which can be prepared bymethods described in [20], as the initial starting material,2-phenyl-ethenesulfonic acid [5-(4-ethyl-phenyl)-6-(2-hydroxy-ethoxy)-pyrimidin-4-yl]-amide was obtained. LC-MS:t_(R)=4.68 min, [M+H]⁺=426.07 (ES+).

Referential Example 16

The precursors depicted in Table 3 below can be prepared according toprocedures published in the literature [1; 2; 3; 6; 9; 10] and accordingto methods described in Referential Examples 1 to 15.

TABLE 3 Structure: LC-MS:

t_(R) = 5.11 [M + H]⁺ = 484.40

t_(R) = 4.35 [M + H]⁺ = 444.15

t_(R) = 4.66 [M + H]⁺ = 458.20

t_(R) = 4.53 [M + H]⁺ = 478.14

t_(R) = 4.13 [M + H]⁺ = 521.08

t_(R) = 4.38 [M + H]⁺ = 522.40

t_(R) = 4.71 [M + H]⁺ = 529.19

t_(R) = 5.21 [M + H]⁺ = 564.13

t_(R) = 4.53 [M + H]⁺ = 522.30

EXAMPLES

The following examples illustrate the invention but do not at all limitthe scope thereof. All temperatures are stated in ° C. Reactions werechecked by TLC and LC-MS. Reaction times can vary from 1 h to severaldays and reaction temperatures can vary from 20° C. to refluxtemperature of THF.

Example 1

To sodium hydride (220 mg, 55-65% in mineral oil) was added THF (35 ml)followed by addition of 2-phenyl-ethenesulfonic acid[6-(2-hydroxy-ethoxy)-5-p-tolyl-pyrimidin-4-yl]-amide (250 mg). Themixture was stirred for 1 h at rt. Then 5-bromo-2-chloro-pyrimidine (188mg) was added and stirring continued for 21 h at 80° C. The solvent wasevaporated and diethylether (20 ml) was added to the residue. Theprecipitate was filtered off and washed with diethylether, dissolved inwater and acidified by citric acid. The precipitate was filtered off andthe crude material was purified by chromatography over silicagel withhexane/EtOAc=1/1 to give 2-phenyl-ethenesulfonic acid{6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]-5-p-tolyl-pyrimidin-4-yl}-amide(91 mg); t_(R)=5.39 (LC); [M+H]⁺=570.34 (ES+); [M−H]⁻=568.45 (ES−).

Example 2

To sodium hydride (26 mg, 55-65% in mineral oil) was added THF (10 ml)followed by the addition of 2-phenyl-ethenesulfonic acid[6-(2-hydroxy-ethoxy)-5-p-tolyl-pyrimidin-4-yl]-amide (100 mg). Themixture was stirred for 1 h at rt. Then 2-chloro-pyrimidine (46 mg) wasadded and stirring continued for 19 h at 80° C. The solvent wasevaporated and diethylether (20 ml) was added to the residue. Theprecipitate was filtered off and washed with diethylether, dissolved inwater and acidified by citric acid. The precipitate was filtered off andthe crude material was purified by chromatography over silicagel withhexane/EtOAc=1/1 to give 2-phenyl-ethenesulfonic acid{6-[2-(pyrimidin-2-yloxy)-ethoxy]-5-p-tolyl-pyrimidin-4-yl}-amide (23.7mg); t_(R)=4.85 (LC); [M+H]⁺=490.27 (ES+).

Example 3

Ethyleneglycol-mono-(4-bromo-phenyl)-ether (112 mg) was dissolved in1,2-dimethoxyethane (5 ml) and potassium tert.-butoxide (50 mg) wasadded and stirring continued for 1 h, followed by the addition of2-phenyl-ethenesulfonic acid [6-chloro-5-p-tolyl-pyrimidin-4-yl]-amide(100 mg) and stirring was continued at 80° C. for 24 h. The reactionmixture was evaporated to dryness, water (20 ml) was added followed byacidification with 10% citiric acid and extraction with ethyl acetate(2×, 20 ml). The combined organic layers were dried over sodium sulfateand the solvent was evaporated. The crude product was recrystallizedfrom 2-propanol and 2-phenyl-ethenesulfonic acid{6-[2-(4-bromo-phenoxy)-ethoxy]-5-p-tolyl-pyrimidin-4-yl}-amide (90 mg)was obtained as a white powder; t_(R)=6.12 (LC); [M−H]⁺=565.75 (ES−).

Example 4

To sodium hydride (65 mg, 55-65% in mineral oil) was added THF (35 ml)followed by the addition of 2-phenyl-ethenesulfonic acid[6-(2-hydroxy-ethoxy)-5-p-tolyl-pyrimidin-4-yl]-amide (200 mg). Themixture was stirred for 1 h at rt. Then 2-chloro-pyrazine (114 mg) wasadded and stirring continued for 18 h at 80° C. The solvent wasevaporated and diethylether (20 ml) was added to the residue. Theprecipitate was filtered off and washed with diethylether, dissolved inwater, acidified by citric acid and extracted with ethyl acetate. Thecombined organic layers were dried over magnesium sulfate andconcentrated in vacuo and the crude material was purified bychromatography over silicagel with hexane/EtOAc=1/1 to give2-phenyl-ethenesulfonic acid{6-[2-)pyrazin-2-yloxy)-ethoxy]-5-p-tolyl-pyrimidin-4-yl}-amide (86.5mg); t_(R)=5.13 (LC); [M+H]⁺=490.21 (ES+).

Example 5

2-Phenyl-ethenesulfonic acid[6-(2-hydroxy-ethoxy)-5-p-tolyl-pyrimidin-4-yl]-amide (150 mg) wasdissolved in THF (10 ml) and sodium hydride (45 mg; 55-65% in mineraloil) was added. The mixture was stirred for 15 min at rt., followed bythe addition of DMF (2 ml) and 2-chloro-5-trifluoromethyl-pyridine (146mg) and heating to 75° C. for 5 h. Then the reaction mixture wasevaporated to dryness and water (15 ml) and citric acid was added. Theprecipitated product was filtered off, washed with water and dried.2-Phenyl-ethenesulfonic acid{5-p-tolyl-6-[2-(5-trifluoromethyl-pyridin-2-yloxy)-ethoxy]-pyrimidin-4-yl}-amide(130 mg) could be obtained as a white powder. t_(R)=5.92 (LC);[M+H]⁺=557.38 (ES+).

Examples 6-240

The corresponding starting materials are treated in a manner accordingto the procedures given in examples 1-5 to give the compounds as listedin Tables 4-45.

TABLE 4 #:Prep. according to Ex:

Ex. No. R¹ R² LC-MS # 6

t_(R) = 6.04 [M + H]⁺:523.22 3 7

t_(R) = 5.55 [M + H]⁺:584.11 1 8

t_(R) = 6.12 [M + H]⁺:582.11 5 9

t_(R) = 5.07 [M + H]⁺:504.20 1 10

t_(R) = 5.22 [M + H]⁺:516.14 1 11

t_(R) = 5.92 [M + H]⁺:569.18 5 12

t_(R) = 5.84 [M + H]⁺:523.22 5

TABLE 5 #: Prep. according to Ex:

Ex. No. R¹ R² LC-MS # 13

t_(R) = 5.14 [M + H]⁺:502.14 1 14

t_(R) = 5.39 [M + H]⁺:524.23 1 15

t_(R) = 5.16 [M + H]⁺:508.23 1 16

t_(R) = 5.53 [M + H]⁺:529.39 1 17

t_(R) = 5.29 [M + M]⁺:495.29 1 18

t_(R) = 5.01 [M + H]⁺:545.24 1 19

t_(R) = 5.17 [M + H]⁺:518.21 1

TABLE 6 #: Prep. according to Ex:

Ex. No. R¹ R² LC-MS # 20

t_(R) = 5.75 [M + H]⁺:598.12 1 21

t_(R) = 5.12 [M + H]⁺:520.03 1 22

t_(R) = 5.09 [M + H]⁺:504.23 1 23

t_(R) = 5.60 [M + H]⁺:584.01 1 24

t_(R) = 5.53 [M + H]⁺:539.53 1 25

t_(R) = 5.26 [M + H]⁺:534.21 1 26

t_(R) = 6.03 [M + H]⁺:583.41 5

TABLE 7 #: Prep. according to Ex:

Ex. No. R¹ R² LC-MS # 27

t_(R) = 5.63 [M + H]⁺:604.31 1 28

t_(R) = 5.30 [M + H]⁺:556.44 1 29

t_(R) = 5.57 [M + H]⁺:559.46 1 30

t_(R) = 5.47 [M + H]⁺:584.39 1 31

t_(R) = 5.43 [M + H]⁺:540.54 1 32

t_(R) = 5.13 [M + H]⁺:534.15 1

TABLE 8 #: Prep. according to Ex:

Ex. No. R¹ R² LC-MS 1# 33

t_(R) = 6.02 [M + H]⁺:598.41 1 34

t_(R) = 5.63 [M + H]⁺:548.26 1 35

t_(R) = 5.96 [M + H]⁺:553.57 1

36

t_(R) = 5.64 [M + H]⁺:583.47 1 37

t_(R) = 5.27 [M + H]⁺:534.19 1 38

t_(R) = 5.59 [M + H]⁺:536.33 1

TABLE 9 #: Prep. according to Ex:

Ex. No. R¹ R² LC-MS # 39

t_(R) = 5.27 [M + H]⁺:534.18 1 40

t_(R) = 5.65 [M + H]⁺:584.30 1

41

t_(R) = 5.63 [M + H]⁺:584.08 1 42

t_(R) = 5.27 [M + H]⁺:534.28 1

TABLE 10 #: Prep. according to Ex:

Ex. No. R¹ R² LC-MS # 43

t_(R) = 5.45 [M + H]⁺:590.01 1 44

t_(R) = 4.95 [M + H]⁺:510.19 1 45

t_(R) = 5.88 [M + H]⁺:577.14 5 46

t_(R) = 5.89 [M + H]⁺:588.38 5 47

t_(R) = 5.36 [M + H]⁺:545.4 1 48

t_(R) = 5.15 [M + H]⁺:541.46 1 49

t_(R) = 5.16 [M + H]⁺:525.44 1

TABLE 11 #: Prep. according to Ex:

Ex. No. R¹ R² LC-MS 1 50

t_(R) = 5.18 [M − H]⁺:526.16 1 51

t_(R) = 5.38 [M + H]⁺:555.98 1

52

t_(R) = 5.65 [M + H]⁺:604.26 1 53

t_(R) = 5.29 [M + H]⁺:555.61 1

TABLE 12 #: Prep. according to Ex:

Ex. No. R¹ R² LC-MS # 54

t_(R) = 5.67 [M + H]⁺:624.20 1 55

t_(R) = 5.34 [M + H]⁺:575.43 1 56

t_(R) = 5.59 [M + H]⁺:579.45 1 57

t_(R) = 5.42 [M + H]⁺:559.50 1

TABLE 13 #: Prep. according to Ex:

Ex. No. R¹ R² LC-MS # 58

t_(R) = 5.61 [M + H]⁺:603.36 1 59

t_(R) = 5.26 [M + H]⁺:555.53 1 60

t_(R) = 5.55 [M + H]⁺:559.52 1 61

t_(R) = 5.46 [M + H]⁺:559.53 1 62

t_(R) = 5.51 [M + H]⁺:604.33 1 63

t_(R) = 5.16 [M + H]⁺:555.57 1

TABLE 14 #: Prep. according to Ex:

Ex. No. R¹ R² LC-MS # 64

t_(R) = 4.98 [M + H]⁺:616.51 1 65

t_(R) = 5.35 [M + H]⁺:667.33 1 66

t_(R) = 5.00 [M + H]⁺:601.51 1

TABLE 15 #: Prep. according to Ex:

Ex. No. R¹ R² LC-MS # 67

t_(R) = 5.34 [M + H]⁺:576.18 1 68

t_(R) = 4.79 [M + H]⁺:496.16 1 69

t_(R) = 5.26 [M + H]⁺:530.32 1 70

t_(R) = 5.79 [M + H]⁺:563.24 5 71

t_(R) = 5.78 [M + H]⁺:574.80 5

TABLE 16 #: Prep. according to Ex:

Ex. No. R¹ R¹⁵ LC-MS # 72

t_(R) = 5.28 [M + H]⁺:653.50 1 73

t_(R) = 5.25 [M + H]⁺:609.35 1 74

t_(R) = 4.93 [M + H]⁺:604.02 1 75

t_(R) = 4.81 [M + H]⁺:588.16 1

TABLE 17 #: Prep. according to Ex:

Ex. No. R¹ R² LC-MS # 76

t_(R) = 5.98 [M + H]⁺:579.41 3 77

t_(R) = 6.09 [M + H]⁺:645.28 3 78

t_(R) = 5.72 [M + H]⁺:565.22 3 79

t_(R) = 4.82 [M + H]⁺:567.20 1 80

t_(R) = 5.45 [M + H]⁺:647.41 1 81

t_(R) = 5.82 [M + H]⁺:646.07 5 82

t_(R) = 5.83 [M + H]⁺:633.87 5

TABLE 18 #: Prep. according to Ex:

Ex. No. R¹ R² LC-MS # 83

t_(R) = 4.93 [M + H]⁺:597.26 1 84

t_(R) = 5.21 [M + H]⁺:602.60 1

TABLE 19 #: Prep. according to Ex:

Ex. No. R¹ R² LC-MS # 85

t_(R) = 5.78 [M − H]⁺:632.25 1 86

t_(R) = 5.33 [M + H]⁺:585.83 1 87

t_(R) = 5.65 [M + H]⁺:589.70 1 88

t_(R) = 5.45 [M + H]⁺:641.33 1 89

t_(R) = 5.39 [M + H]⁺:596.31 1 90

t_(R) =5.09 [M + H]⁺:591.74 1

TABLE 20 #: Prep. according to Ex:

Ex. No. R¹ R² LC-MS # 91

t_(R) = 4.78 [M + H]⁺:476.23 1 92

t_(R) = 5.30 [M + H]⁺:556.16 1 93

t_(R) = 5.68 [M + H]⁺:543.34 5 94

t_(R) = 5.68 [M + H]⁺:554.95 5 95

t_(R) = 5.30 [M + H]⁺:544.13 1 96

t_(R) = 4.87 [M + H]⁺:506.14 1

TABLE 21 #: Prep. according to Ex:

Ex. No. R¹ R² LC-MS # 97

t_(R) = 5.14 [M − H]⁺:538.09 1 98

t_(R) = 4.96 [M − H]⁺:508.36 1 99

t_(R) = 5.46 [M + H]⁺:590.22 1

TABLE 22 #: Prep. according to Ex:

Ex. No. R¹ R² LC-MS # 100

t_(R) = 5.39 [M + H]⁺: 522.30 1 101

t_(R) = 5.95 [M + H]⁺: 602.20 1 102

t_(R) = 6.18 [M − H]⁺: 608.71 5 103

t_(R) = 5.33 [M + H]⁺: 544.21 1 104

t_(R) = 6.03 [M + H]⁺: 633.49 1 105

t_(R) = 5.97 [M + H]⁺: 588.00 1 106

t_(R) = 5.71 [M + H]⁺: 582.35 1

TABLE 23

Ex. No. R¹ R² LC-MS # 107

t_(R) = 5.14 [M + H]⁺: 634.06 1 108

t_(R) = 5.02 [M + H]⁺: 589.66 1 109

t_(R) = 5.08 [M + H]⁺: 633.65 1 110

t_(R) = 4.69 [M + H]⁺: 583.04 1 111

t_(R) = 5.06 [M + H]⁺: 634.35 1 112

t_(R) = 4.73 [M + H]⁺: 584.08 1 113

t_(R) = 5.42 [M + H]⁺: 629.77 1

TABLE 24

Ex. No. R¹ R² LC-MS # 114

t_(R) = 5.46 [M + H]⁺: 585.59 1 115

t_(R) = 5.25 [M + H]⁺: 629.36 1 116

t_(R) = 6.25 [M + H]⁺: 639.64 1 117

t_(R) = 5.83 [M + H]⁺: 678.29 1

TABLE 25

Ex. No. R¹ R² LC-MS # 118

t_(R) = 5.24 [M + H]⁺: 586.07 1 119

t_(R) = 4.94 [M + H]⁺: 536.12 1 120

t_(R) = 5.19 [M + H]⁺: 540.33 1 121

t_(R) = 4.91 [M + H]⁺: 520.49 1 122

t_(R) = 4.73 [M + H]⁺: 506.09 1 123

t_(R) = 5.70 [M + H]⁺: 573.09 5 124

t_(R) = 5.67 [M + H]⁺: 584.89 5

TABLE 26

Ex. No. R¹ R² LC-MS # 125

t_(R) = 5.44 [M + H]⁺: 648.30 1 126

t_(R) = 5.11 [M + H]⁺: 598.31 1 127

t_(R) = 5.85 [M + H]⁺: 655.22 1 128

t_(R) = 5.42 [M + H]⁺: 605.26 1 129

t_(R) = 5.33 [M + H]⁺: 575.41 1 130

t_(R) = 6.26 [M + H]⁺: 642.16 5 131

t_(R) = 6.28 [M + H]⁺: 654.03 5

TABLE 27

Ex. No. R¹ R² LC-MS # 132

t_(R) = 6.01 [M + H]⁺: 610.22 1 133

t_(R) = 5.59 [M + H]⁺: 560.25 1 134

t_(R) = 5.92 [M − H]⁺: 562.15 1 135

t_(R) = 5.51 [M + H]⁺: 530.33 1 136

t_(R) = 6.48 [M + H]⁺: 608.32 5 137

t_(R) = 6.44 [M + H]⁺: 597.12 5

TABLE 28

Ex. No. R¹ R² LC-MS # 138

t_(R) = 5.66 [M + H]⁺: 583.99 1 139

t_(R) = 5.30 [M + H]⁺: 534.18 1 140

t_(R) = 5.23 [M + H]⁺: 648.19 1 141

t_(R) = 4.85 [M + H]⁺: 568.32 1 142

t_(R) = 5.63 [M + H]⁺: 646.77 5 143

t_(R) = 5.68 [M + H]⁺: 635.30 5 144

t_(R) = 5.02 [M + H]⁺: 598.01 1

TABLE 29

Ex. No. R¹ R² LC-MS # 145

t_(R) = 5.28 [M + H]⁺: 653.50 1 146

t_(R) = 4.93 [M + H]⁺: 604.02 1 147

t_(R) = 5.25 [M + H]⁺: 608.35 1 148

t_(R) = 4.81 [M + H]⁺: 588.16 1

TABLE 30

Ex. No. R¹ R² LC-MS # 149

t_(R) = 5.14 [M + H]⁺: 680.44 1 150

t_(R) = 4.71 [M + H]⁺: 630.28 1 151

t_(R) = 4.73 [M + H]⁺: 614.10 1 152

t_(R) = 4.65 [M + H]⁺: 600.44 1 153

t_(R) = 5.68 [M + H]⁺: 678.22 3 154

t_(R) = 5.41 [M + H]⁺: 598.40 3 155

t_(R) = 4.96 [M + H]⁺: 634.34 1

TABLE 31

Ex. No. R¹ R² LC-MS # 156

t_(R) = 5.21 [M + H]⁺: 713.22 1 157

t_(R) = 4.93 [M + H]⁺: 686.05 1 158

t_(R) = 4.43 [M − H]⁺: 604.09 1

TABLE 32

Ex. No. R¹ R² LC-MS # 159

t_(R) = 5.37 [M + H]⁺: 679.43 1 160

t_(R) = 4.74 [M + H]⁺: 629.29 1 161

t_(R) = 4.77 [M + H]⁺: 613.27 1 162

t_(R) = 4.74 [M + H]⁺: 599.61 1 163

t_(R) = 5.88 [M + H]⁺: 677.15 3 164

t_(R) = 5.01 [M + H]⁺: 635.53 1 165

t_(R) = 5.61 [M + H]⁺: 666.22 5

TABLE 33

Ex. No. R¹ R² LC-MS # 166

t_(R) = 5.00 [M + H]⁺: 634.49 1 167

t_(R) = 5.24 [M + H]⁺: 667.15 1 168

t_(R) = 5.57 [M + H]⁺: 678.32 5 169

t_(R) = 5.27 [M + H]⁺: 692.74 1 170

t_(R) = 4.75 [M + H]⁺: 613.00 1 171

t_(R) = 5.29 [M + H]⁺: 691.18 1 172

t_(R) = 4.95 [M + H]⁺: 643.14 5

TABLE 34

Ex. No. R¹ R² LC-MS # 173

t_(R) = 4.86 [M + H]⁺: 685.03 1 174

t_(R) = 4.47 [M + H]⁺: 605.26 1 175

t_(R) = 5.18 [M + H]⁺: 693.40 1 176

t_(R) = 5.34 [M + H]⁺: 648.62 1 177

t_(R) = 4.99 [M + H]⁺: 643.27 1 178

t_(R) = 4.93 [M + H]⁺: 685.38 1 179

t_(R) = 4.53 [M + H]⁺: 635.10 1

TABLE 35

Ex. No. R¹ R² LC-MS # 180

t_(R) = 4.49 [M + H]⁺: 605.06 1 181

t_(R) = 4.78 [M − H]⁺: 636.93 1

TABLE 36

Ex. No. R¹ R² LC-MS # 182

t_(R) = 5.38 [M + H]⁺: 679.55 1 183

t_(R) = 4.91 [M + H]⁺: 630.30 1 184

t_(R) = 4.99 [M + H]⁺: 614.36 1 185

t_(R) = 4.86 [M + H]⁺: 600.53 1 186

t_(R) = 5.97 [M + H]⁺: 678.31 3 187

t_(R) = 5.15 [M + H]⁺: 635.52 1 188

t_(R) = 5.69 [M + H]⁺: 667.04 5

TABLE 37

Ex. No. R¹ R² LC-MS # 189

t_(R) = 4.93 [M + H]⁺: 600.24 4 190

t_(R) = 5.80 [M + H]⁺: 679.24 5 191

t_(R) = 5.09 [M − H]⁺: 597.21 5 192

t_(R) = 5.30 [M + H]⁺: 668.00 1

TABLE 38

Ex. No. R¹ R² LC-MS # 193

t_(R) = 5.84 [M + H]⁺: 687.43 1 194

t_(R) = 5.28 [M + H]⁺: 607.56 1 195

t_(R) = 5.58 [M + H]⁺: 642.98 1 196

t_(R) = 5.36 [M + H]⁺: 625.34 1 197

t_(R) = 5.31 [M + H]⁺: 637.23 1 198

t_(R) = 5.66 [M + H]⁺: 675.29 1 199

t_(R) = 6.05 [M + H]⁺: 674.16 5

TABLE 39

Ex. No. R¹ R² LC-MS # 200

t_(R) = 6.08 [M + H]⁺: 685.94 5 201

t_(R) = 5.94 [M + H]⁺: 720.81 1 202

t_(R) = 5.76 [M − H]⁺: 698.38 1 203

t_(R) = 5.42 [M + H]⁺: 651.39 1 204

t_(R) = 5.51 [M + H]⁺: 652.91 1

TABLE 40

Ex. No. R¹ R² LC-MS # 205

t_(R) = 6.04 [M + H]⁺: 642.29 1 206

t_(R) = 5.54 [M + H]⁺: 562.48 1 207

t_(R) = 5.64 [M + H]⁺: 576.37 1 208

t_(R) = 5.60 [M + H]⁺: 616.00 1 209

t_(R) = 5.14 [M + H]⁺: 536.45 1 210

t_(R) = 5.88 [M + H]⁺: 722.31 1

TABLE 41

Ex. No. R¹ R² LC-MS # 211

t_(R) = 5.35 [M + H]⁺: 601.87 1 212

t_(R) = 4.84 [M + H]⁺: 522.29 1 213

t_(R) = 5.21 [M + H]⁺: 556.23 1 214

t_(R) = 5.25 [M + H]⁺: 607.35 1 215

t_(R) = 4.88 [M + H]⁺: 558.45 1 216

t_(R) = 5.77 [M + H]⁺: 589.04 5 217

t_(R) = 5.84 [M + H]⁺: 601.06 5

TABLE 42

Ex. No. R¹ R² LC-MS # 218

t_(R) = 5.46 [M + H]⁺: 615.95 1 219

t_(R) = 5.10 [M + H]⁺: 566.34 1 220

t_(R) = 5.11 [M + H]⁺: 549.82 1 221

t_(R) = 4.88 [M + H]⁺: 541.82 1 222

t_(R) = 5.24 [M + H]⁺: 568.19 1 223

t_(R) = 5.15 [M + H]⁺: 566.23 1 224

t_(R) = 5.45 [M + H]⁺: 616.59 1

TABLE 43 #: Prep. according to Ex:

Ex. No. R¹ R² LC-MS # 225

t_(R) = 5.34 [M + H]⁺: 635.80 1 226

t_(R) = 5.00 [M + H]⁺: 586.49 1 227

t_(R) = 5.24 [M − H]⁺: 601.44 1 228

t_(R) = 5.16 [M + H]⁺: 713.06 1 229

t_(R) = 4.84 [M + H]⁺: 663.16 1

TABLE 44 #: Prep. according to Ex:

Ex. No. R¹ R² LC-MS # 230

t_(R) = 5.19 [M + H]⁺: 602.26 1 231

t_(R) = 4.71 [M + H]⁺: 522.07 1 232

t_(R) = 5.14 [M + H]⁺: 568.20 1 233

t_(R) = 4.90 [M + H]⁺: 552.19 1 234

t_(R) = 5.36 [M + H]⁺: 616.25 1 235

t_(R) = 5.47 [M + H]⁻: 564.14 1

TABLE 45 #: Prep. according to Ex: Ex. No. R¹ R² LC-MS #

236

t_(R) = 4.99 [M − H]⁺: 677.26 1 237

t_(R) = 4.65 [M + H]⁺: 629.16 1 238

t_(R) = 5.14 [M + H]⁺: 693.08 1 239

t_(R) = 4.81 [M + H]⁺: 643.08 1

240

t_(R) = 5.54 [M + H]⁺: 684.45 1 241

t_(R) = 5.21 [M + H]⁺: 637.28 1

Example 242

Using methods described in the above Examples and in schemes 1 to 3 andthe cited references, the compounds disclosed in Table 46 can beprepared:

TABLE 46

R¹: R²: R⁴:

Example 243

Using methods described in the above Examples and in schemes 1 to 3 andin the cited references, the compounds disclosed in Table 47 can beprepared:

TABLE 47

R¹: R²: R⁴:

List of Abbreviations:

-   CyHex cyclohexane-   DCM dichloromethane-   DMF dimethylformamide-   DMSO dimethylsulfoxide-   EA ethyl acetate-   Hex hexane-   HV high vacuum conditions-   MCPBA m-chloroperbenzoic acid-   min minutes-   rt room temperature-   THF tetrahydrofuran-   t_(R) retention time

1. A compound of the formula I

wherein R¹ and R² are individually aryl or heteroaryl; R³ is phenyl,mono-, di- or tri-substituted phenyl substituted with lower alkyl, loweralkenyl, lower alkynyl, phenyl, lower alkyloxy, amino, lower alkylamino,amino-lower alkyl, trifluoromethyl, trifluoromethoxy, halogen, loweralkylthio, hydroxy, hydroxy-lower alkyl, cyano, carboxyl, loweralkanoyl, formyl, benzofuranyl, aryl or heteroaryl; R⁴ is hydrogen,halogen, trifluoromethyl, lower alkyl, lower alkyl-amino, loweralkyloxy, lower alkyl-sulfono, lower alkyl-sulfinyl, lower alkylthio,lower alkylthio-lower alkyl, hydroxy-lower alkyl, lower alkyl-oxy-loweralkyl, hydroxy-lower alkyl-oxy-lower alkyl, hydroxy-lower alkyl-amino,lower alkyl-amino-lower alkyl, amino, di-lower alkyl-amino,[N-(hydroxy-lower alkyl)-N-(lower alkyl)]-amino, aryl, aryl-amino,aryl-lower alkyl-amino, aryl-thio, aryl-lower alkyl-thio, aryloxy,aryl-lower alkyl-oxy, aryl-lower alkyl, aryl-sulfinyl, heteroaryl,heteroaryl-oxy, heteroaryl-lower alkyl-oxy, heteroaryl-amino,heteroaryl-lower alkyl-amino, heteroaryl-thio, heteoroaryl-loweralkyl-thio, heteroaryl-lower alkyl, heteroaryl-sulfinyl, heterocyclyl,heterocyclyl-lower alkyl-oxy, heterocyclyl-oxy, heterocyclyl-amino,heterocyclyl-lower alkyl-amino, heterocyclyl-thio, heterocyclyl-loweralkyl-thio, heterocyclyl-lower alkyl, heterocyclyl-sulfinyl, cycloalkyl,cycloalkyl-oxy, cycloalkyl-lower alkyl-oxy, cycloalkyl-amino,cycloalkyl-lower alkyl-amino, cycloalkyl-thio, cycloalkyl-loweralkyl-thio, cycloalkyl-lower alkyl, cycloalkyl-sulfinyl; R⁵ and R⁶ areindividually hydrogen or lower alkyl; X is oxygen, sulfur, NH, CH₂ or abond; Y is oxygen, sulfur or —NH—; Z is oxygen, sulfur, —NH— or a bond;Q is —(CH₂)_(n) or —(CH₂)_(m)—C≡C—(CH₂)_(p)—, and when p is the wholenumber 0, Z is a bond or —CH₂-cyclopropylen-CH₂—; n is the whole numbers2, 3, 4, 5 or 6; m is the whole numbers 1, 2 or 3; p is the wholenumbers 0, 1, 2 or 3; or pharmaceutically acceptable salts thereof. 2.The compounds of claim 1, wherein R¹, R², R⁴, R⁵, R⁶, Q, Y and Z are asdefined in claim 1, X, is oxygen and R³ is phenyl or mono-substitutedphenyl substituted with halogen, lower alkyl, lower alkylene loweralkoxy, amino, lower alkyl-amino, lower alkyl-thio, hydroxy,hydroxymethyl or lower alkanoyl.
 3. The compounds of claim 1, whereinR¹, R², R⁴, R⁵, R⁶ and Q are as defined in claim 1, X, Y and Z representindividually oxygen and R³ is di-substituted phenyl substituted withhalogen or lower alkoxy.
 4. The compounds of claim 1, wherein R¹, R²,R⁴, R⁵, R⁶ and Q are as defined in claim 1, X, V and Z are individuallyoxygen and R³ is mono-substituted phenyl substituted with halogen, loweralkyl or lower alkoxy.
 5. The compounds of claim 1, wherein R¹, R², R⁴,R⁵ and R⁶ are as defined in claim 1, X, V and Z are individually oxygen,Q is —(CH₂)_(n)— with n=2 and R³ is phenyl, mono- or di-substitutedphenyl substituted with halogen, lower alkyl or lower alkoxy.
 6. Thecompounds of claim 1, wherein R¹, R⁴, R⁵ and R⁶ are as defined in claim1, X, Y and Z are individually oxygen, Q is —(CH₂)_(n)— with n=2 R² isheteroaryl and R³ is phenyl, mono- or di-substituted phenyl substitutedwith halogen, lower alkyl or lower alkoxy.
 7. The compounds of claim 1having the formula:

wherein R¹, R², R³, R⁴, R⁵, R⁶, Y, Q and Z are as defined in claim 1, orpharmaceutically acceptable salts thereof compound.
 8. The compound ofclaim 1 having the formula:

wherein R¹, R², R⁴, R⁵, R⁶, Y, Q and Z are as defined in claim 1 and Tis a chlorine-, a bromine- or a hydrogen-atom or a methyl group or amethoxy group or pharmaceutically acceptable salts thereof.
 9. Thecompounds of claim 7 having the formula:

wherein R¹, R², R³, R⁴ and Q are as defined in claim 1 orpharmaceutically acceptable salts thereof.
 10. The compound of claim 8having the formula:

wherein R¹ and R² are as defined in claim 1 and T is chlorine-, abromine- or a hydrogen-atom or a methyl group or a methoxy group orpharmaceutically acceptable salts thereof.
 11. The compound of claim 10,wherein R² is heteroaryl or pharmaceutically acceptable salts thereof.12. The compound of claim 1 wherein said compound is one of thefollowing: 2-Phenyl-ethenesulfonic acid[6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]-5-p-tolyl-pyrimidin-4-yl]-amide;2-Phenyl-ethenesulfonic acid{5-(4-bromo-phenyl)-6-[2-(5-bromo-pyrimi-din-2-yloxy)-ethoxy]-pyrimidin-4-yl}-amide;2-Phenyl-ethenesulfonic acid{6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]-5-phenyl-pyrimidin-4-yl}-amide;2-Phenyl-ethenesulfonic acid{6-[2-(5-chloro-pyrimidin-2-yloxy)-ethoxy]-5-p-tolyl-pyrimidin-4-yl}-amide;2-Phenyl-ethenesulfonic acid{6-[2-(4-bromo-phenoxy)-ethoxy]-5-p-tolyl-pyrimidin-4-yl}-amide;2-Thiophen-3-yl-ethenesulfonic acid{6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]-5-p-tolyl-pyrimidin-4-yl}-amide;2-Thiophen-2-yl-ethenesulfonic acid{6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]-5-p-tolyl-pyrimidin-4-yl}-amide;2-Thiophen-2-yl-ethenesulfonic acid{6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]-5-p-tolyl-[2,2′]bipyrimidinyl-4-yl)-amide;2-Phenyl-ethenesulfonic acid{6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]-5-p-totyl-[2,2′]bipyrimidinyl-4-yl)-amide;2-Phenyl-ethenesulfonic acid(6-[2-(5-bromo-pyrimidin-2-yioxy)-ethoxy]-5-(2-methoxy-phenoxy)-pyrimidin-4-yl]-amide;2-Phenyl-ethenesulfonic acid[6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]-5-(3-methoxy-phenoxy)-pyrimidin-4-yl]-amide;2-Phenyl-ethenesulfonic acid[6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]-5-(2-methoxy-phenoxy)-2-pyrazin-2-yl-pyrimidin-4-yl]-amide;2-Phenyl-ethenesulfonic acid[6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]-5-(2-methoxy-phenoxy)-2-morpholin-4-yl-pyrimidin-4-yl]-amide;2-Phenyl-ethenesulfonic acid{5-(2-methoxy-phenoxy)-2-morpholin-4-yl-6-[2-(5-trifluoromethyl-pyrimidin-2-yloxy)-ethoxy]-pyrimidin-4-yl}-amide;2-Phenyl-ethenesulfonic acid{5-(2-methoxy-phenoxy)-6-[2-(pyrimidin-2-yloxy)-ethoxy]-[2,2′]bipyrimidinyl-4-yl}-amide;2-Thiophen-2-yl-ethenesulfonic acid[6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]-5-(2-methoxy-phenoxy)-[2,2′]bipyrimidinyl-4-yl]-amide;2-Thiophen-2-yl-ethenesulfonic acid[6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]-5-(2-methoxy-phenoxy)-2-pyridin-4-yl-pyrimidin-4-yl]-amide;2-Phenyl-ethenesulfonic acid[6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]-5-(2-chloro-5-methoxy-phenoxy)-pyrimidin-4-yl]-amide;2-Phenyl-ethenesulfonic acid[6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]-5-(4-chloro-phenyl)-pyrimidin-4-yl]-amide;2-Phenyl-ethenensulfonic acid}6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]-2-pyridin-4-yl-5-p-tolyl-pyrimidin-4-yl}-amide;or pharmaceutically acceptable salts thereof.
 13. The compound of claim11 wherein R¹ is phenyl.
 14. The compound of claim 13 wherein saidcompound is 2-phenyl-ethenesulfonic acid[6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]-5-(4-chloro-phenyl)-pyrimidin-4-yl]-amideor pharmaceutically acceptable salts thereof.
 15. The compound of claim13 wherein said compound is 2-phenyl-ethenesulfonic acid{6-[2-(5-bromo-primidin-2-yloxy)-ethoxy]-2-pyridin-4-yl-5-p-tolyl-pyrimidin-4-yl}-amideor pharmaceutically acceptable salts thereof.
 16. The compound of claim13 wherein said compound is 2-phenyl-ethenesulfonic acid[6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]-5-p-tolyl-pyrimidin-4-yl]-amideor pharmaceutically acceptable salts thereof.
 17. The compound of claim13 wherein said compound is 2-phenyl-ethenesulfonic acid{5-[4-bromo-phenyl)-6-[2-(5-bromo-pyrimi-din-2-yloxy)-ethoxy]-pyrimidin-4-yl}-amideor pharmaceutically acceptable salts thereof.
 18. The compound of claim13 wherein said compound is 2-phenyl-ethenesulfonic acid{6-[2-(5-chloro-pyrimidin-2-yloxy)-ethoxy]-5-p-tolyl-pyrimidin-4-yl}-amideor pharmaceutically acceptable salts thereof.
 19. The compound of claim11 wherein R¹ is heteroaryl.
 20. The compound of claim 19 wherein saidcompound is 2-thiophen-3-yl-ethenesulfonic acid{6-(2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]-5-p-tolyl-pyrimidin-4-yl}-amideor pharmaceutically acceptable salts thereof.
 21. The compound of claim19 wherein said compound is 2-thiophen-2-yl-ethenesulfonic acid{6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]-5-p-tolyl-pyrimidin-4-yl}-amideor pharmaceutically acceptable salts thereof.
 22. The compound of claim10 wherein R² is aryl.
 23. The compound of claim 22 wherein saidcompound is 2-phenyl-ethenesulfonic acid{6-[2-(4-bromo-phenoxy)-ethoxy]-5-p-tolyl-pyrimidin-4-yl}-amide orpharmaceutically acceptable salts thereof.
 24. The compound of claim 8wherein R¹ is phenyl and R⁴ is heteroaryl.
 25. The compound of claim 24where said compound is 2-phenyl-ethenesulfonic acid{6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]-5-p-tolyl-[2,2′]bipyrimidinyl-4-yl}-amideor pharmaceutically acceptable salts thereof.
 26. The compound of claim8 wherein is R¹ heteroaryl.
 27. The compound of claim 24 wherein saidcompound is 2-thiophen-2-yl-ethenesulfonic acid{6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]-5p-tolyl-[2,2′]bipyrimidinyl-4-yl}-amideor pharmaceutically acceptable salts thereof.
 28. The compound of claim6 wherein R¹ is aryl.
 29. The compound of claim 28 wherein said compoundis 2-phenyl-ethenesulfonic acid[6-[2-(5bromo-pyrimidin-2-yloxy)-ethoxy]-5-(2methoxy-phenoxy)-pyrimidin-4-yl]-amideor pharmaceutically acceptable salts thereof.
 30. The compound of claim28 wherein said compound is 2-phenyl-ethenesulfonic acid[6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]-5-(3-methoxy-phenoxy)-pyrimidin-4-yl]-amideor pharmaceutically acceptable salts thereof.
 31. The compound of claim28 wherein said compound is 2-phenyl-ethenesulfonic acid[6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]-5-(2-methoxy-phenoxy)-2-pyrazin-2-yl-pyrimidin-4-yl]-amideor pharmaceutically acceptable salts thereof.
 32. The compound of claim28 wherein said compound is 2-phenyl-ethenesulfonic acid[6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]-5-(2-methoxy-phenoxy)-2-morpholin-4-yl-pyrimidin-4-yl]-amideor pharmaceutically acceptable salts thereof.
 33. The compound of claim28 wherein said compound is 2-phenyl-ethenesulfonic acid{5-(2-methoxy-phenoxy)-2-morpholin-4-yl-6-[2-(5-trifluoromethyl-pyrimidin-2-yloxy)-ethoxy]-pyrimidin-4-yl}-amideor pharmaceutically acceptable salts thereof.
 34. The compound of claim28 wherein said compound is 2-phenyl-ethenesulfonic acid{5-(2-methoxy-phenoxy)-6-[2-(pyrimidin-2yloxy)-ethoxy]-[22′]bipyrimidinyl-4-yl}-amide or pharmaceutically acceptable saltsthereof.
 35. The compound of claim 28 wherein said compound is2-phenyl-ethenesulfonic acid[6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]-5-(2-chloro-5-methoxy-phenoxy)-pyrimidin-4-yl]-amideor pharmaceutically acceptable salts thereof.
 36. The compound of claim6 wherein R¹ is heteroaryl.
 37. The compound of claim 36 wherein saidcompound is 2-thiophen-2-yl-ethenesulfonic acid[6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]-5-(2-methoxy-phenoxy)-[2,2′]bipyrimidinyl-4-yl]-amideor pharmaceutically acceptable salts thereof.
 38. The compound of claim36 wherein said compound is 2-thiophen-2-yl-ethenesulfonic acid[6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]-5-(2-methoxy-phenoxy)-2-pyridin-4-yl-pyrimidin-4-yl]-amideor pharmaceutically acceptable salts thereof.